Dugan L L, Turetsky D M, Du C, Lobner D, Wheeler M, Almli C R, Shen C K, Luh T Y, Choi D W, Lin T S
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9434-9. doi: 10.1073/pnas.94.17.9434.
Two regioisomers with C3 or D3 symmetry of water-soluble carboxylic acid C60 derivatives, containing three malonic acid groups per molecule, were synthesized and found to be equipotent free radical scavengers in solution as assessed by EPR analysis. Both compounds also inhibited the excitotoxic death of cultured cortical neurons induced by exposure to N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or oxygen-glucose deprivation, but the C3 regioisomer was more effective than the D3 regioisomer, possibly reflecting its polar nature and attendant greater ability to enter lipid membranes. At 100 microM, the C3 derivative fully blocked even rapidly triggered, NMDA receptor-mediated toxicity, a form of toxicity with limited sensitivity to all other classes of free radical scavengers we have tested. The C3 derivative also reduced apoptotic neuronal death induced by either serum deprivation or exposure to Abeta1-42 protein. Furthermore, continuous infusion of the C3 derivative in a transgenic mouse carrying the human mutant (G93A) superoxide dismutase gene responsible for a form of familial amyotrophic lateral sclerosis, delayed both death and functional deterioration. These data suggest that polar carboxylic acid C60 derivatives may have attractive therapeutic properties in several acute or chronic neurodegenerative diseases.
合成了两种具有C3或D3对称性的水溶性羧酸C60衍生物的区域异构体，每个分子含有三个丙二酸基团，通过电子顺磁共振（EPR）分析评估发现它们在溶液中是等效的自由基清除剂。两种化合物还抑制了因暴露于N-甲基-D-天冬氨酸（NMDA）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）或氧-葡萄糖剥夺所诱导的培养皮质神经元的兴奋毒性死亡，但C3区域异构体比D3区域异构体更有效，这可能反映了其极性性质以及随之而来的进入脂质膜的更强能力。在100微摩尔浓度下，C3衍生物甚至能完全阻断迅速引发的NMDA受体介导的毒性，这种毒性形式对我们测试过的所有其他类别的自由基清除剂敏感性有限。C3衍生物还减少了血清剥夺或暴露于β淀粉样蛋白1-42所诱导的凋亡性神经元死亡。此外，在携带导致一种家族性肌萎缩侧索硬化症的人类突变（G93A）超氧化物歧化酶基因的转基因小鼠中持续输注C3衍生物，延缓了死亡和功能恶化。这些数据表明，极性羧酸C60衍生物在几种急性或慢性神经退行性疾病中可能具有诱人的治疗特性。
